Calmodulin kinase II-dependent transactivation of PDGF receptors mediates astrocytic MMP-9 expression and cell motility induced by lipoteichoic acid

Background: lipoteichoic acid (lta) is a component of gram-positive bacterial cell walls,which has been found to be elevated in cerebrospinal fluid of patients suffering from meningitis. moreover,matrix metalloproteinases (mmps),mmp-9 especially,have been observed in patients with brain inflammatory diseases and may contribute to brain disease pathology. however,the molecular mechanisms underlying lta-induced mmp-9 expression in brain astrocytes remain unclear.objective: the goal of this study was to examine whether lta-induced cell migration is mediated by calcium/calmodulin (cam)/cam kinase ii (camkii)-dependent transactivation of the pdgfr pathway in rat brain astrocytes (rba-1 cells).methods: expression and activity of mmp-9 induced by lta was evaluated by zymographic,western blotting,and rt-pcr analyses. mmp-9 regulatory signaling pathways were investigated by treatment with pharmacological inhibitors or using dominant negative mutants or short hairpin rna (shrna) transfection,and chromatin immunoprecipitation (chip)-pcr and promoter activity reporter assays. finally,we determined the cell functional changes by cell migration assay.results: the data show that c-jun/ap-1 mediates lta-induced mmp-9 expression in rba-1 cells. next,we demonstrated that lta induces mmp-9 expression via a calcium/cam/camkii-dependent transactivation of pdgfr pathway. transactivation of pdgfr led to activation of pi3k/akt and jnk1/2 and then activated c-jun/ap-1 signaling. activated-c-jun bound to the ap-1-binding site of the mmp-9 promoter,and thereby turned on transcription of mmp-9. eventually,up-regulation of mmp-9 by lta enhanced cell migration of astrocytes.conclusions: these results demonstrate that in rba-1 cells,activation of c-jun/ap-1 by a camkii-dependent pi3k/akt-jnk activation mediated through transactivation of pdgfr is essential for up-regulation of mmp-9 and cell migration induced by lta. understanding the regulatory mechanisms underlying lta-induced mmp-9 expression and functional changes in astrocytes may provide a new therapeutic strategy for gram-positive bacterial infections in brain disorders. © 2010 wang et al; licensee biomed central ltd.